1. Field of the Invention
The present invention provides novel intermediates for making lubiprostone.
2. Description of the Related Art
Lubiprostone, 7-[(1R,3R,6R,7R)-3-(1,1-difluoropentyl)-3-hydroxy-8-oxo-2-oxabicyclo[4.3.0]non-7-yl]heptanoic acid, is the active pharmaceutical ingredient (API; drug substance) in the drug product Amitiza®, a gastrointestinal agent used for the treatment of Chronic Idiopathic Constipation in adults. It is marketed by Sucampo Pharmaceuticals, Inc. and was approved by the United States Food and Drug Administration (FDA) on Jan. 31, 2006. It is also approved by FDA to treat Irritable Bowel Syndrome with constipation (ISB-C) in adult women aged 18 and over on Apr. 29, 2008. Amitiza® is also being clinically tested for other gastrointestinal disorders. Lubiprostone is a bicyclic 13,14-dihydro-15-keto-16,16-difluoro-prostaglandin E1 derivative (a.k.a., a so-called 13,14-dihydro-15-keto-prostaglandin derivative). Prostaglandins possess the prostanoic acid backbone which is a C20 fatty acid (FIG. 1).
The existence of an electron deficient ketone at C15, along with a conveniently positioned hydroxyl group at C11 results in lubiprostone existing predominantly in a bicyclic form that includes a 6-membered hemiketal ring. This form exists in equilibrium with a monocyclic form (Scheme 1). Taken together, these two forms are referred to as tautomeric isomers. In sugar chemistry this kind of equilibrium of cyclic and acyclic forms is referred to as ring-chain tautomerisation (R-CT).1 Whereas in D2O, the ratio of the bicyclic form to monocyclic form is 6:1, in CDCl3 it is 96:4.2 Despite this tautomerisation and the predominance of the bicyclic hemiketal form, lubiprostone is still referred to as a 15-keto-prostaglandin E1 derivative. According to US2010056808A1 the two crystalline polymorphs of lubiprostone reported exist as the bicyclic form in the solid state. 1 According to http://en.wikipedia.org/wiki/Tautomer, ring-chain tautomerisation “occurs when the movement of the proton is accompanied by a change from an open structure to a ring, such as the open chain and pyran forms of glucose.”

An early approach with great versatility for the synthesis of prostaglandins and analogues was invented by E. J. Corey3 in the late 60's and this is probably the strategy most used by industry. To date, besides the presently claimed process, it is the only method that has been disclosed for lubiprostone synthesis. This approach is referred to as the “Corey method”. The Corey lactone aldehyde (a.k.a., Corey aldehyde),4 which itself requires many synthetic steps, is central to the Corey approach and contains all of the three PGE1 stereochemical centres (such as those required in lubiprostone) already in place, and the ω- and α-side chains are added sequentially by Horner-Wadsworth-Emmons (or HWE reaction) and Wittig reactions (Scheme 2). In the Corey approach, the order of addition of the α- and ω-side chains is interchangeable. 2 U.S. Pat. No. 7,355,064 B2.3 J. Am. Chem. Soc., 1969, 91, 5675-5676.4 Angew. Chem. Int. Ed. Engl., 1991, 30, 455-465.
